US3920664A

US3920664A - D-2-halo-6-alkyl-8-substituted ergolines and related compounds

Info

Publication number: US3920664A
Application number: US419566A
Authority: US
Inventors: James A Clemens; Edmund C Kornfeld; Nicholas J Bach
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1972-07-21
Filing date: 1973-11-28
Publication date: 1975-11-18
Anticipated expiration: 1992-11-18

Abstract

D-2-halo-6-alkyl-8-substituted ergolines and related compounds, prolactin inhibitors.

Description

United States Patent Clemens et al.

[ Nov. 18, 1975 D-2-HALO-6-ALKYL-8-SUBSTITUTED ERGOLINES AND RELATED COMPOUNDS Inventors: James A. Clemens; Edmund C.

Kornfeld; Nicholas J. Bach, all of Indianapolis, Ind.

Assignee: Eli Lilly and Company, Indianapolis,

Ind.

Filed: Nov. 28, 1973 Appl. No.: 419,566

Related US. Application Data Continuation-impart of Ser. No. 273,902, July 21, v

1972, abandoned.

US. Cl. 260/285.5; 424/261; 424/250; I

y 260/268 PE Int. Cl. C07D 457/02 Field of Search 260/285.5

' OTHER PUBLICATIONS Fluckiger et a1.; Chem. Abstr. Vol. 70, p; 2199R (1969).

Primary Examiner-Donald G. Daus Assistant Examiner-Mary C. Vaughn Attorney, Agent, or FirmJames L. Rowe; Everet F.

, Smith [57] ABSTRACT D-2-halo-'6-alkyI-8-substituted ergolines and 'related compounds, prolactin inhibitors.

8 Claims, No Drawings BACKGROUND OF THE INVENTION Compounds based on the ergoline ring system (1):

have a suprising variety of pharmaceutical activities. For example, lysergic and isolysergic acid are 8-carboxy-6-methyl-A -ergolines. The amides of lysergic acid, many of which have valuable and unique pharmacologic properties, include the naturally occurring oxy tocic alkaloids ergocornine, ergokryptine, ergonovine, ergocristine, ergosine, ergotamine etc.- and synthetic oxytocics such as methergine as well as the synthetic hallucinogen lysergic acid diethylamide or LSD. The amides of 6-methyl-8-carboxyergoline,

known generically as dihydroergot alkaloids, are oxytocic agents of lower potency and also lower toxicity than the ergot alkaloids themselves. Ergotamine, a A -ergoline, has been used in the treatment of migraine and recently, both ergocomine and 2-bromo-a-ergokryptine have been shown to be inhibitors of prolactin and of dimethylbenzanthracene (DMBA)-induced tumors in rats, according to Nagasawa and Meites, Proc. Soc. Exptl. Biol. Med. 135, 469 (1970) and to Heuson et al., Europ. J. Cancer, 353 (1970). (See also US. Pat. Nos. 3,752,888 and 3,752,814).

D-6-methyl-8-cyanomethylergoline was first prepared by Semonsky and co-workers, Coll. Czech. Chem. Commun., 33, 577 (1968), and its use'in preventing pregnancy in rats was published by the same group in Nature, 221, 666 (1969). (See also US. Pat. No. 3,732,231) The compound was thought to interfere with the secretion of hypophysial leuteotropic hormone and the hypophysial gonadotropins. It was also suggested that the compound inhibited the secretion of prolactin. [See Seda et al., Reprod. Fert., 24, 263 (1971) and Mantle and Finn, id. 44l) Semonsky and co-workers, Coll. Czech. Chem. Cmm., 36, 220 (1971 described the preparation of D-6-methyl-8- ergolinylacetamide, a compound which is stated to have anti-fertility and anti-lactating effects on rats. The effect of these compounds in neoplastic disease is unknown.

Ergolines having a group other than methyl in the 6- position have been prepared. by Fehr et al., HelwChim. Acta, 53, 2197 (1971) and Nakaharo et al., Chem. Pharm. Bull., 19, 2337 (197-1).

' benzoate,

SUMMARY OF THE INVENTION U v This invention provides a group of novel-D-6.-alkyl 2,8-disubstituted ergolines represented by the following formula: v

wherein X is Cl, Br, 1, CH or CN; R is CHQ-CN or and R is C C primary alkyl, H or CN.

Also included within the scope of this invention are the non-toxic salts of the above ergoline bases formed with pharmaceutically-acceptable acids.

In the above formula, when R is C -C primary alkyl, it represents methyL'ethyl, n-propyl, n-butyl and isobutyl. Y

The prefix D in the naming of thecompoundsof the above structure indicates that the stereochernistry of the ergoline derivative is identical to that of D-lysergic acid-the naturally-occurring form.

Non-toxic salts of the ergolines represented by the above formula can be formed with both organic andinorganic pharmaceutically-acceptable acids. Such salts include sulfates, such as sulfate, pyrosulfate, and bisulfate; sulfites, such as sulfite and bisulfite; nitrate; phosphates, such as phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate and pyrophosphate; halides, such as chloride, bromide and iodide; C C aliphatic carboxylates, such as acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate and propiolate; C,-C aliphatic dicarboxylates, such as oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butynel,4-dioate and hexyne-1,6-dioate; benzoates, such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate and methoxybenzoate; phthalates, such as phthalate and terephthalate; arylsulfonates, such as tolue nesulfonate, benzenesulfonate, naphthalenesulfonate, p-chlorobenzenesulfonate and xylenesulfonate; citrate; C -C a-hydroxyalkanoates,

such as lactate, B-hydroxybutyrate and glycollate,

tion of N'-bromosuccinimide, N-chlorosuccinimide or other positive halogenating agent on D-6-methyl-8-,

cyanom'ethylergoline, or D-6-methyl-8-carboxamidomethylergolineprepared by the methods of Se- 3 monsky and co-workers (loc. cit.). Alternatively, compounds in which R is CH CN and R is methyl can be prepared by 'the reaction of a positive halogenating agent on a D-6-methyl-8-halomethylergoline followed by replacement of the halogen atom of the halomethyl group with a cyano group, using sodium cyanide or like reagent to effect the displacement. Conversion of the thus formed cyano group to an amide group can be carried out by procedures well known in the art. Similar halogenation of D-6-methyl-8-mesyloxymethyl (or 8- tosyloxymethyl)ergoline in the 2-position readily yields an intermediate which will react with sodium cyanide or other like inorganic cyanide in an inert solvent to yield compounds coming within the scope of the above formula. Compounds in which both X and R are methyl are prepared by reacting D-6-methyl-8- cyanomethyl (or 8-carboxamidomethyl)ergoline with methyl formate and ethanedithiol to yield the dithioethylene acetal of a D-2-formyl-6-methyl-8-substituted ergoline. Desulfurization of the resulting dithioacetal yields the desired 2-methyl derivative. [P. Stutz and D. A. Stadler, Helv. Chim. Acta, 55, 75 (1972).] Again, alternatively, a 6-methyl-8-bromomethylergoline can be formylated in the 2-position in the presence of ethanedithiol to yield the dithioacetal of the 2-formyl derivative. Desulfurization of the dithioacetal to yield the Z-methyl derivative followed by reaction of the bromomethyl group with sodium cyanide provides compounds of the desired stnicture. Those compounds in which X is cyano and R is methyl are prepared by reaction of a 2-unsubstituted ergoline with chlorosul- 'fonylisocyanate and triethylamine [H. Vorbruggen,

Tetrahedron Letters 1631 (1968) 1 Compounds in which R is other than methyl are preferably prepared by reacting with cyanogen bromide, a compound in which X and R are defined as above and R is methyl. A suitable inert solvent such as methylene dichloride is customarily used. The product of this reaction is 6-cyano derivative in which the groups at 8 and 2 r main unchanged. Reduction or bydrolysis of the 6-cyano derivative produces the secondary amine compound (111) III in which X and R are defined as hereinabove. Alkylation of this secondary amine by an alkyl halide (R'-Hal wherein Hal is preferably chloro, bromo or iodo) in a suitable inert solvent produces a compound of formula 11 above. The above procedure is useful not only in preparing the hitherto unavailable '6-alkyl ergolines wherein the alkyl group is other than methyl but is also useful in the case where the alkyl group (R) is methyl in preparing radioactive-labled-ergoline derivatives of formula 11 above in which the radioactive tag is a C atom located in the C methyl group. Alternatively, the methyl group of a D-6-methyl-8-substituted ergoline can be replaced with a higher alkyl group by the above procedure to'yield a D-6-alkyl-8-substituted ergoline, which latter compound can then be halogenated or otherwise substituted in the 2-position of the ergoline ring by the procedures set forth above for the 6-methyl egolines to yield 6-alkyl compounds of Formula II above, in which R is other than methyl.

This invention is further illustrated by the following specific examples.

EXAMPLE 1 Preparation of D-2-chloro-6-methyl-S-cyanomethylergoline Four-hundred milligrams of N-chlorosuccinimide were dissolved in 30 ml. of dioxane and the solution added in dropwise fashion at a temperature of about 60C. to a stirred suspension of 535 mg. of D-6-methyl- 8-cyanomethylergoline dissolved in 25 ml. of dioxane. After the addition had been completed, the reaction mixture was heated under a nitrogen atmosphere in the range 6065C. for a period of about 4.5 hours. The reaction mixture was then cooled and diluted with water. Solid sodium bicarbonate was added to the mixture which was then extracted with chloroform. The chloroform layer was separated and dried, and the chloroform removed by evaporation in vacuo. The resulting crude residue showed the presence of 2 spots on thin-layer chromatography. The residue was therefore dissolved in chloroform and chromatographed over florisil. Thinlayer chromatography carried out on each of the chloroform eluate fractions indicated that fractions 7-12 had the largest amounts of a new component, (not starting material). The fractions showing a relatively large amount of this new component by thin-layer chromatography were combined and the chloroform evaporated therefrom. The resulting residue, on recrystallization from ether, yielded mg. of D-2-chloro-6- methyl- 8-cyanomethylergoline melting at 2703C.

Analysis: Calc: C, 68.11; H, 6.05; H, 14.02; Cl, 11.83. Found: C, 67.82; H, 6.14; N, 13.81; Cl, 11.77.

Following the above procedure, D-6-methyl-8- cyanomethylergoline was brominated with N- bromosuccinimide to yield D-2-bromo-6-methyl-8- cyanomethylergoline melting at about 244-7C. with decomposition after recrystallization from ethanol.

Analysis: Calc: C, 59.31; H, 5.27; N, 12.21; Br, 23.21; Found: C, 59.33; H, 5.37; N, 11.96; Br, 23.39.

Following the above procedure, D-6-methyl-8- cyanomethylergoline was reacted with N-iodosuccinimide to yield D-2-iodo-6-methyl-8-cyanomethylergoline melting at about 21 l213C. with decomposition after recrystallization from ether.

Analysis: Calc: C, 52.19; H, 4.64; N, 10.74; I, 32.44; Found: C, 51.90; H, 4.51; N, 10.58; I, 32.17.

EXAMPLE 2 Preparation of D-2-cyano-6-methyl-8-cyanomethylergoline Following the procedure of H. Vorbruggen, Tetrahedron Letters, 1631 (1968), 325 mg. of D-6-methyl-8- carbomethoxyergoline were dissolved in 40 ml. of acetonitrile. A solution containing 310 mg. of chlorosulfonylisocyanate in 10 ml. of acetonitrile was added rapidly in dropwise fashion to the original solution. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for about 68 hours. Thin layer chromatography on an aliquot of the reaction indicated the presence of a material less polar than starting material. About 3 ml. of triethylamine were added and the resulting mixture stirred for about 3 hours. The reaction mixture was then poured into saturated aqueous sodium bicarbonate and the resulting mixture extracted with ethyl acetate. The ethyl acetate layer was separated, washed several times with an equal volume of water, washed once with an equal volume of saturated aqueous sodium chloride, separated and then dried-.- Evaporation of the solvent therefrom yielded a residue which was dissolved in chloroform, and the resulting solution chromatographed over 20 g. of florisil. Development of the chromatogram with chloroform containing 2 percent ethanol yielded two fractions of about 150 ml. each which contained D-2-cyano-6methyl-8- carbomethoxyergoline synthesized in the above reaction. The solvents were evaporated from the combined fractions and the residue recrystallized from a mixture of ether and hexane. D-2-cyano-6-methyl-8-carbomethoxyergoline thus prepared melted at about 2101 1C. with decomposition.

Analysis: Calc: C, 69.88; H, 6.19; N, 13.58; Found: C, 70.16; H, 6.36; N, 13.77.

Reduction of the above carbomethoxy derivative with sodium borohydride readily yields the corresponding D-2-cyano-6-methyl-8-hydroxymethylergoline. Reaction of the hydroxy group with methanesulfonylchloride by a procedure set forth hereinafter in Example 6 readily yields the mesylate derivative of the 8-hydroxymethyl group. Reaction of the mesylate with sodium cyanide as set forth in Example 7 for the reaction between an 8-bromomethyl.compound and sodium cyanide readily yields D-2-cyano-6-methyl-8-cyanomethylergoline.

EXAMPLE 3 Preparation of D-2,6-dimethyl- 8-cyanomethylergoline About 2.6 g. of D-6-methyl-8-cyanomethylergoline were dissolved in 100 ml. of chloroform to which had been added 50 ml. of methyl formate. 1.84 g. of ethanedithiol were next added. A solution of 4.4 m1. of titanium tetrachloride in 50 ml. of chloroform was added in a slow stream to the previously prepared solution. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for about 63 hours, and was then cooled to about 0C. Twenty-five ml. of methanol were added. The reaction mixture was made basic with N aqueous ammonium hydroxide. The organic layer was separated, washed with saturated aqueous sodium bicarbonate, again separated and 6 An aqueous suspension of W-6 Raney nickel was washed with ethanol until the water had been displaced by ethanol. 19 ml. aliquot of this ethanol suspension was itself suspended in a mixture of 16 ml. each of dimethylformamide (DMF) and of acetone. To this solution was added a solution of 1.7 g. of D-2-(1',3'-

dithiacyclopentan-2 '-yl )-6-methyl-8-cyanomethylergodried. Evaporation of the solvent in vacuo left as a resiby evaporation in vacuo, and the resulting residue crystallized from ether to yield D-2-(1',3-dithiacyclopentan-2'-yl)-6-methyl-8-cyanomethylergoline melting at about 239242C. with decomposition.

Analysis: Calc: C, 65.00; H, 6.27; N, 11.37; S, 17.35; Found: C, 64.73; H, 6.02; N, 11.12; S, 17.38.

line in ml. of acetone and 70 ml. of DMF. The mixture was stirred at room temperature for about 1.5 hours. The Raney nickel catalyst was separated by filtration, and the filter cake washed several times with acetone. The filtrate was then diluted with water and with aqueous sodium bicarbonate. The filtrate was next extracted with chloroform, the chloroform layer separated and dried, and the chloroform evaporated therefrom invacuo. The resulting residue was diluted with water to yield a yellow oil which was dissolved in ethyl acetate. The ethyl acetate solution was separated,

EXAMPLE 4 Preparation of D-2bromo-6-methyl-8 -carboxamidomethylergoline 15.04; Found:

A solution containing 240 mg. of D-6-methyl-8-carboxamidoergoline and 25 ml. of dioxane was prepared at a temperature in the range 6570C. under a nitrogen atmosphere. A solution containing 180 mg. of N- bromosuccinimide in 20 ml. of dioxane was added in dropwise fashion. The resulting mixture was heated at the same temperature range with stirring for about onehalf hour and was then poured over saturated aqueous tartaric acid. The resulting mixture was extracted with chloroform, and the chloroform layer discarded. The aqueous layer was filtered and then made basic with dilute ammonium hydroxide. D-2-bromo-6-methyl-8-carboxamidomethylergoline formed in the above reaction was insoluble in the aqueous alkaline solution and separated. The separated compound was dissolved in chloreform. The chloroform layer was separated and dried. Evaporation of the solvents in vacuo yielded D-2- bromof6-methyl-8-carboxamidomethylergoline which melted at about 238241C. with decomposition after crystallization from ether.

EXAMPLE 5 Preparation of D-6-methyl-8-bromomethylergoline A solution of 5.2 g. of triphenylphosphine dissolved in ml. of acetonitrile was placed under a nitrogen atmosphere and stirring initiated. 1.0 ml. of bromine was'a'dded in dropwise fashion to the triphenyphos-.

phine solution. After the addition had been completed slight warming yielded a clear, colorless solution indicating completion of the reaction. 505 mg. of D-6- methyl-8-hydroxymethylergoline was added all at once to the triphenylphosphoniumbromide solution. The reaction mixture was stirred for about 6.5 hours at room temperature protected by a calcium chloride drying tube. The solution was then poured into saturated aqueous sodium bicarbonate and the organic material extracted with chloroform. The chloroform layer was then contacted with saturated aqueous tartaric acid, thereby forming water-soluble tartrate salts of the ergoline bases present. The water layer was separated, the chloroform layer being discarded. The water layer was then made basic with solid sodium bicarbonate. The ergoline base, being insoluble in the aqueous alkaline solution, separated and was dissolved in chloroform. The chloroform layer was separated and dried. Evaporation of the chloroform in vacuo yielded a residue comprising D-6-methyl-8-bromomethylergoline formed in the above reaction.

Analysis: Calc: C, 60.20; H, 6.00; N, 8.78; Br, 25.03; Found: C, 6011;1-1, 6.06; N, 8.59; Br, 25.35.

EXAMPLE 6 Preparation of D-6-methyl-8-cyanomethylergoline A suspension of 10 g. of D-6-methyl-8-hydroxymethylergoline in 200 ml. of pyridine was prepared. To this suspension was added slowly a solution containing 6.0 ml. of methanesulfonyl chloride and 200 ml. of pyridine. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for about one half hour and was then poured into 2.5 l. of saturated aqueous sodium bicarbonate. The alkaline aqueous layer was diluted to 6 liters with water and the diluted layer allowed to stand at room temperature. D-6-methyl-8-mesyloxymethylergoline formed in the above reaction crystallized. The solution was chilled to about C. in order to cause more of the desired material to precipitate. The solution was then filtered and the filter cake recrystallized from ethanol. A furtherquantity of D-6-methyl-8-mesyloxymethylergoline was obtained by extracting the filtrate with ethyl acetate, separating the ethyl acetate layer and removing the ethyl acetate by evaporation in vacuo. Recrystallization of D-6 methyl- 8-mesyloxymethylergoline prepared as above from ethanol yielded material melting at about l92-4C. with decomposition.

Analysis: Calc: C, 61.05; H, 6.63; N, 8.38; S, 9.59; Found: C, 60.85; H, 6.46; N, 8.45; S, 9.30.

12.5 g. of D-6-methyl-8-mesyloxymethylergoline prepared as above was heated with 12 g. of sodium cyanide in the presence of 350 ml. of DMSO at 100l05C. under a nitrogen atmosphere for 45 minutes. The reaction mixture was poured into 2.1 1. of saturated aqueous sodium chloride and the resulting mixture filtered. The solid material thus obtained was slurried in warm water and refiltered to give about 8.4 g. of D-6-methyl- 8cyanomethylergoline.

EXAMPLE 7 Alternate preparation of D-2-bro mo-6-methyl- 8-cyanomethylergoline A solution of 955 mg. of D-6-methyl-8-bromomethylergoline, prepared by the procedure of Example 5, in 50 ml. of dioxane was heated to 6065C. under a nitrogen atmosphere. A solution of 600 mg. of N- bromosuccinimide in 70 ml. of dioxane was added in dropwise fashion. The reaction mixture was heated at 6065C. for an additional half hour after allthe N- bromosuccinimide had been added. The reaction mixture was then cooled and aqueous tartaric acid added thus forming water-soluble tartrate salts of the ergoline bases present. The resulting mixture was extracted with chloroform, and the chloroform layer discarded. The aqueous layer was filtered and then made basic by the addition of solid sodium bicarbonate in which the ergoline bases were insoluble. The aqueous layer was extracted with chloroform and the chloroform layer separated and dried, and the chloroform removed by evaporation in vacuo. Chromatography of the resulting residue over florisil using chloroform as the eluant yielded fractions containing, as a predominant spot on thinlayer chromatography, a material other than starting material. These .fractions were combined, the solvent removed by evaporation in vacuo, and the resulting residue recrystallized from ether to yield D-2-bromo-6- methyl-8-bromomethylergoline produced in the above reaction. The compound melted at about 215C. with decomposition.

Analysis: Calc: C, 48.27; H, 4.56; N, 7.04; Br, 40.14; Found: C, 48.01, H, 4.66, N, 7.16; Br, 40.38.

mg. of D-2-bromo-6-methyl-8-bromomethylergoline prepared as above were dissolved in 10 ml. of dimethylsulfoxide (DMSO). mg. of sodium cyanide were added and the resulting mixture heated at C. under a nitrogen atmosphere for about 45 minutes. The reaction mixture was cooled, diluted with water and filtered. The filter cake was dissolved in an ethanolchloroform solvent mixture, and the solvents removed by evaporation in vacuo. Recrystallization of theresidue from ether yielded D-2-bromo-6-methyl-8- cyanomethylergoline prepared in the above reaction. The compound melted at about 2403C. with decomposition.

Following the above procedure, D-6-methyl-8- rnesyloxymethylergoline (from Example 6) can be halogenated in the 2-position by the procedure of Example 1 to yield D-2-chloro-6-methyl-8-mesyloxymethylergoline, D-2-bromo-6-methyl-8-mesyloxymethylergoline or D-2-iodo-6-methyl-8-mesyloxymethylergoline, each of which can in turn be converted to the 8-cyanomethy1 derivative by reaction with sodium cyanide as above.

The 8-tosyloxyrnethyl derivatives, prepared by substituting p-toluenesulfonyl chloride for methanesulfonyl chloride in the procedure of Example 6, can be halogenated in the 2-position and the 2-halo derivative reacted with sodium cyanide to yield the same compounds.

. EXAMPLE 8 Preparation D-2-chloro-6-ethyl-8-cyanomethylergoline A solution was prepared containing 6.11 g. of D-2- chloro-6-methyl-8-cyanomethylergoline (as furnished by the procedure of Example 1) in 1000 ml. of methylenedichloride. 13.5 g. of cyanogen bromide were Analysis calc: C, 65.70; H, 4.87; N, 18.03; Cl, 1.1.41;

Found: C, 65.46; H, 4.61; N, 18.01; Cl, 11.49.

A mixture of 5.4 g. of D-2-chloro-6-cyano-8- cyanomethylergoline, 30 g. of zinc dust, 2210 ml. of glacial acetic acid and 45 ml. of water was refluxed under a nitrogen atmosphere for 8 hours. The reaction mixture was filtered, and the filtrate diluted with water and then made basic by the addition of MN aqueous ammonium hydroxide. The alkaline solution was extracted with chloroform, the chloroform layer separated, washed with water and dried, and the chlorofomr evaporated therefrom by evaporation in vacuo. The resulting residue, comprising D-2-chloro-8-cyanomethylergoline formed in the above reaction, was recrys tallized from ethanol to yield crystals melting at 228-9C. with decomposition. I

Analysis calc: 67.24; H, 5.64; N, 14.70; Cl, 12.41; Found: C, 66.99; H, 5.40; N, 14.87; Cl, 12.42.

About 300 mg. of D-2-chloro-8-cyanomethylergoline were dissolved in 10 ml. of DMF (dimethylformamide). 220 mg. of potassium carbonate were added to the reaction mixture, followed by 0.12 ml. of ethyl iodide. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 5.5 hours. The reaction mixture was then diluted with water, and the aqueous layer extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water, followed by a wash with saturated aqueous sodium chloride and was then dried. Evaporation of the ethyl acetate in vacuo yielded D-2-chloro-6-ethyl-8-cyanomethylergoline melting at 225-7C. with decomposition after chromatography over florisil using chloroform containing 2 percent ethanol as the eluting solvent.

Analysis calc.: C, 68.89; H, 6.42; N, 13.39; Cl, 11.30; Found: C, 68.64; H, 6.15; N, 13.45; Cl, 11.37.

Following the above procedure but substituting the appropriate alkyl halide for ethyl iodide, the following compound was prepared: D-2-chloro-6-n-propyl-8- cyanomethylergoline melting at 185-7C.

Analysis calc.: C, 69.61; H, 6.76; N, 12.82; Cl, 10.81; Found: C, 69.57; H, 6.98; N, 12.59; Cl, 10.64.

Alkylation of D-2-chloro-8-cyanomethylergoline with methyl iodide in the presence of potassium carbonate in DMF solution yields D-2-chloro-6-methyl-8- cyanomethylergoline. The compound has identical properties to the starting material provided for this series of reactions in Example 1.

Following the above procedure, D-2-chloro-6-methyl-8-carboxamidomethylergoline has been demethylated, and the resulting secondary amine alkylated to yield higher alkyl analogs as, for example, D-2- chloro-6-ethyl-8-carboxamidomethylergoline and D-2- chloro-6-n-propyl-8-carboxamidomethylergoline. Similarly 8-cyanomethyl or 8-carboxamidomethylergolines having groups in the 2 position of the ergoline ring other than chloro as, for example, the 2-bromo, 2-iodo, 2-methyl or 2-cyano derivatives, can also be demethylated to yield the corresponding secondary amine which compound can in turn be realkylated to yield higher homologs as in the D-2-chloro-8-cyanomethyl reaction series outlined above in Example 8.

Salts of the compounds of this invention (Formula 11 above) with pharmaceutically-acceptable acids can be prepared by dissolving a quantity of the particular ergoline base in ether and adding the pharmaceuticallyacceptable acid in an equivalent amount also in ethanol solution. In this instance, the salts are generally soluble and are recovered by removal of the solvent by evapo- 10 ration in vacuo. The resulting residue, if not crystalline, can be readily crystallized from ethanol or other suitable solvent.

Preparation of Salts A solution containing 560 mg. of D-2-bromo-6-methyl-8-cyanomethylergoline in about 40 ml. of tetrahydrofuran (THF) was prepared. About 10 ml. of a solution prepared by dissolving 1 g. of maleic acid in 50 ml. of THF was added with stirring to the solution of the ergoline base. About 200 ml. of ether were added, and the resulting precipitate separated by filtration. D-2- bromo-6-methyl-8-cyanomethylergoline acid maleate thus prepared melted at about 207209C. with decomposition.

Following the above procedure, D-2-chloro-6-methyl-8-cyanomethylergoline acid maleate was prepared melting at about 204206C. with decomposition.

Following the above procedure, 320 mg. of D-2- chloro-6-methyl-S-cyanomethylergoline were dissolved in 15 ml. of THF. To this solution was added a solution of methanesulfonic acid in THF, 1 drop at a time, until the addition of a drop gave no further precipitate. The THF solution was diluted with ether, and the resulting mixture filtered to yield the methanesulfonic acid salt of D-2-chloro-6-methyl-8-cyanomethylergoline melting at about 295C. with decomposition after recrystallization from an ethanol-ether solvent mixture.

Analysis: Calc: C, 54.61; H, 5.60; N, 10.61; Cl, 8.95; S, 8.10; Found: C, 54.43; H, 5.79; N, 10.86; Cl, 9.22; S, 8.18.

Following the above procedure, 220 mg. of D-2- chloro-6-methyl-8-cyanomethylergoline were dissolved in 15 ml. of THF. An excess of a saturated solution of d-tartaric acid in THF was added. A gelatinous precipitate resulted which slowly crystallized. The mixture was diluted with ether and filtered to yield the tartrate salt of D-2-chloro-6-methyl-8-cyanomethylergoline melting at about 2479C. after recrystallization from an ethanol-ether solvent mixture.

Analysis: Calc.: C, 60.88; H, 5.65; N, 11.21; Cl, 9.46; Found: C, 60.66; H, 5.41; N, 11.41; Cl, 9.49.

The compounds of this invention are useful as gonadotropin inhibitors. As such they inhibit lactation and are specifically prolactin inhibitors. The compounds are useful in the treatment of inappropriate lactation such as postpartum lactation and galactorrhea. In addition, the compounds can be used to treat prolactindependent adenocarcinomas and prolactin-secreting pituitary tumors as Well as the following disorders: Forbes Albright syndrome, Chiari Frommel syndrome, gynecomastia itself and gynecomastia occurring as a result of estrogenic steroid administration for prostatic hypertrophy, fibrocystic disease of the breast (benign nodules), prophylactic treatment of breast cancer, and breast development resulting from the administration of psychotropic drugs, for example, thorazine, or for prostatic hypertrophy itself.

In carrying out my novel control method, using the compounds of this invention to inhibit prolactin secretion, a 2,8-disubstituted-6=alkylergoline according to Formula 11 above, wherein R is other than H or CN, or a salt thereof with a pharmaceutical]y-acceptable acid is suspended in corn oil and the suspension injected parenterally or fed to a female mammal in amounts varying from 0.01 to 10 mg/kg/day of mammalian weight. 'Oral administration is preferred. If parenteral administration is used, the injection is preferably by the 1 l subcutaneous route using an appropriate pharmaceutical formulation although other modes of parenteral administration such as intraperitoneal, intramuscular, or intravenous routes are equally effective. In particular,

12 Experiments designed to show the activity of compounds of this invention in suppressing the growth of adenocarcinomas in female mammals is demonstrated by the following experiment in which, for illustrative with intravenous or intramuscular administration, asolpurposes only, rats were used as exemplary of adenouble pharmaceutically-acceptable salt of a Z-substitutcarcinoma-susceptible female mammals. The determied-6-alkyl-8cyanomethyl-ergoline, preferably the nation was carried out as follows: methanesulfonate salt, is customarily employed. For Mammary tumors were induced in rats by a single oral administration, a compound according to Formula oral feeding of 20 mg. of 7,l2-dimethylbenzanthracene II (wherein R is C -C primary alkyl) either as the free (DMBA). The mammary glands were palpated for tubase of in the form of a salt thereof can also be mixed mors at weekly intervals. Rats were selected for experiwith standard pharmaceutical excipients and loaded mentation when they had at least one measurable into empty telescoping gelatin capsules or pressed into tumor about 0.5 cm. in diameter. The animals with tutablets. mors were divided into groups of 5 and treated daily The inhibition of prolactin secretion by the comwith various doses of a D-2-halo-6-methyl8-cyanomepounds of this invention is evidenced by the following thylergoline suspended in corn oil. One group of conexperiment: Groups of lactating postpartum female rats trol rats was treated with corn oil only. The results are were administered drug at 4 to 8 days postpartum (degiven in Table 2. In the table, column 1 gives the name livery equals day 0). A control group received only 0.2 of the compound under test, column 2 gives the dose ml. of corn oil daily, and other groups received D-2- employed, column 3 gives the route of administration, bromo-6-methyl-8-cyanomethylergoline or the correcolumn 4 the original tumor diameter, column 5 the sponding chloro compound at different dose levels. At tumor diameter after 12 days of treatment, and column the beginning of treatment, the rat litters were reduced 6 gives the percent change. to six pups each and the total weight of each litter re- Table 2 corded. Both litters and lactatmg females were weighed on days 4, 6, and 8. On day 8 the lactating females were T diameter taken from their suckling litters and immediately de- O i i l ft l2 capltated. The blood was collected and the resulting N f D R t f t y of Percent serum assayed by a radioimmunoassay for prolactin 2:3 a g T; E i "53: 1?" Change content. The table which follows records results of this D 2 b 5 S C 6 7 7 8 experiment. In the Table, column I gives the treatment administered, column 2 the number of rats in the cyanomethyl 7 5.0 7.7 5.6 27 treated group, column 3 the average weight changes of game 5 P O H 7 I l the reduced litter, column 4 the average body weight l0 PiOi 7:7 4:5 42

Control, 0.2 change of the lactatmg female, and column 5 the aver ml com on P04 7.0 89 +27 age serum prolactin levels on day 8. vehicle Table 1 Treatment No. of Avg. Weight Change Avg. Body Weight Avg. Serum Prolactin (Day 4 Day 8 Rats of Reduced Litter Change of Lactating Levels of Lactating post partum) (Day 4 Day 8) Female Females (Day 8) Control Corn Oil 30 +43.8 i 1.9 gm +l I.3 i 3.2 gm 60.6 i 4.8 ng/ml (0.2 ml/da) D-2-Bromo-6-methyl-8B cyanomethyl-ergolinel 1 +24.9 4.2*gm +18.5 t 5.1 gm 11.9 i 1.9 ng/ml* (0.6 mg/da) D-2-Bromo-6-methyl-8B- cyanomethyl-ergoline 10 +148 I 2.0*gm 3.9 4.0 gm 12.4 i 1.3 nglml*a (1.0 mg/da) D-2-Chloro-6-methyl-8B- V cyanomethyl-ergoline l l 5.5 2.6*gm 0.9 1' 4.7 gm 11.8 i 1.0 ng/ml* (0.6 mg/da) Significantly different from controls P .00] Not significantly different aThis value based on 5 animals D-2-chloro 5 SC 7.5 5.3 29 As can be seen from the above table, the two comy z- 7 s C 6 3 4 8 24 pounds coming within the scope of Formula II above y i greatly decreased the prolactin levels and thus the pro- 5 5. A 2.; -37 1 38 Iactin secretion in the lactating female rats.

Other compounds coming within the scope of formula II above wherein R is C -C primary alkyl are extremely effective prolactin inhibitors, showing an inhibition of prolactin comparable to that given in Table l for D-2-bromo-6-methyl-8-cyanomethylergoline and D-2-chloro-6methyl-8cyanomethylergoline. In particular, the 6-ethyl and 6-n-propyl analogs showed a comparable prolactin inhibition. activity to that of the 6- methyl compound.

*S.C. Subcutaneous "R0. by mouth decreased toxicity as compared with those compounds of the prior art in which the 2-position is unsubstituted. For example, acute toxicity studies in mice indicate that the D-2-halo-6-methyl-8-cyanomethyl (or 8-carboxamidomethyl)-ergolines have an LD in the neighborhood of l ,000 mg/kg. On the other hand, D-6-methyl-8-cyanomethylergoline has an LD of about 100 mg/kg in mice. Acid addition salts of D-2-halo-6-alkyl- 8-cyanomethyl(or 8-carboxamidomethyl)-ergolines are somewhat more toxic then the free bases since they are more readily absorbed. For example, D-2-chloro-6- methyl-8-cyanomethylergoline methane sulfonate had an acute oral toxicity as follows: LD =250-3OO mg./kg. Furthermore, daily subcutaneous doses to mice as high as 7 mg./kg. showed little or no toxicity as shown by loss of weight. As prolactin inhibitors, however, the 2- halo substituted compounds of this invention were at least equally potent to the unsubstituted D-6-methyl-8- cyanomethyl (or S-carboxamidomethyl)ergolines of the prior art.

We claim: 1. Compounds of the formula wherein X is Cl, Br, 1, CH or CN, R is CH CN or and R is C -C primary alkyl, H or CN and non-toxic salts thereof formed with pharmaceutically-acceptable acids.

2. A compound according to claim 1 in which R is C C. primary alkyl and R and X are as defined.

3. A compound according to claim 1, said compound being D-2-chloro-6-methyl-S-cyanomethylergoline.

4. A compound according to claim 1 said compound being D-2-bromo-6-methyl-8-cyanomethylergoline.

5. A compound according to claim 1, said compound being D-2-bromo-6-methyl-8-carboxamidomethylergoline.

6; A compound according to claim 1, said compound being D-2-chl0ro-6-methyl-8-cyanomethylergoline methanesulfonate.

7. D-6-methyl-8-mesyloxymethylergoline.

8. An intermediate compound according to claim I, in which R is H or CN and R and X are as defined.

Claims

1. COMPOUNDS OF THE FORMULA

2. A compound according to claim 1 in which R'' is C1-C4 primary alkyl and R and X are as defined.

3. A compound according to claim 1, said compound being D-2-chloro-6-methyl-8-cyanomethylergoline.

6. A compound according to claim 1, said compound being D-2-chloro-6-methyl-8-cyanomethylergoline methanesulfonate.

7. D-6-methyl-8-mesyloXymethylergoline.

8. An intermediate compound according to claim 1, in which R'' is H or CN and R and X are as defined.